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6
Oclassen Clinical Trial R90-001-01 (NIH Protocol 91-AI-0031)

Once they had determined that the maximum tolerated dose (MTD) of FIAC was without any significant effect on cytomegalovirus (anti-CMV), the investigators hypothesized that minor metabolites of FIAC might be responsible for the toxic effects associated with the drug, particularly the nausea, vomiting, and fatigue. The in vitro anti-CMV activity of the major metabolite, FIAU, was virtually identical to that of FIAC, allowing the possibility of finding a dose of FIAU which would inhibit CMV while producing fewer or less severe adverse effects than FIAC. Acute single-dose animal toxicity data were available demonstrating normal transaminase levels in rats and only minimal elevations in cynomolgus monkeys (see Appendix F for details). Results of multiple-dose studies done in rats (28 days) and dogs (10 days) were available, but long-term dosage studies in animals had not been done as yet. As a result the investigators planned a traditional Phase I, dose-escalating study of FIAU, with the emphasis being placed strictly on safety and not anti-CMV activity. Therefore, patients were no longer required to have CMV in their blood or urine to be eligible for participation in the study. This allowed human immunodeficiency virus (HIV)-infected patients with higher CD4 counts to be entered into the trial.

The development of R90-001-01 was very similar to the development of R89. Multiple meetings and conference calls within the AIDS Clinical Trials Group system reviewed draft protocols, including reviews by representatives from the Medical Branch of the National Institute of Allergy and Infectious Diseases (NIAID) and the Food and Drug Administration (FDA). The protocol was originally designed to establish FIAU as a potential anti-CMV drug. HIV-infected patients were to receive FIAU syrup three times daily at dosages of either 1.0, 1.7, 3.0, or 5.0 mg/kg/day. Cohorts of 10 patients each were to be enrolled successively in each dosage group, beginning at the 1 mg/kg/day dosage.

During protocol development, several reviewers suggested evaluating the potential role of FIAU in the treatment of hepatitis B virus (HBV) infection, citing the potent in vitro activity of both FIAC and FIAU against HBV (Hantz, Allaudeen, Ooka, De Clercq and Trepo, 1984). FIAC also had been shown more effective than Ara-A in reducing circulating viral DNA in woodchucks infected with a HBV closely related to that infecting man (Fourel, Hantz, Watanabe, Jacquet, Chomel and Trepo, 1990). By mid-August, an amendment was created (Amendment 1) which allowed investigators to enroll HBV infected persons after an initial cohort of non-HBV infected individuals had been enrolled. Based on the knowledge that patients with chronic HBV infection often have chronic elevations in their liver enzymes, Amendment 1 also changed the AST entry criterion to allow patients with up to 5 times the



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Review of the Fialuridine (FIAU) Clinical Trials 6 Oclassen Clinical Trial R90-001-01 (NIH Protocol 91-AI-0031) Once they had determined that the maximum tolerated dose (MTD) of FIAC was without any significant effect on cytomegalovirus (anti-CMV), the investigators hypothesized that minor metabolites of FIAC might be responsible for the toxic effects associated with the drug, particularly the nausea, vomiting, and fatigue. The in vitro anti-CMV activity of the major metabolite, FIAU, was virtually identical to that of FIAC, allowing the possibility of finding a dose of FIAU which would inhibit CMV while producing fewer or less severe adverse effects than FIAC. Acute single-dose animal toxicity data were available demonstrating normal transaminase levels in rats and only minimal elevations in cynomolgus monkeys (see Appendix F for details). Results of multiple-dose studies done in rats (28 days) and dogs (10 days) were available, but long-term dosage studies in animals had not been done as yet. As a result the investigators planned a traditional Phase I, dose-escalating study of FIAU, with the emphasis being placed strictly on safety and not anti-CMV activity. Therefore, patients were no longer required to have CMV in their blood or urine to be eligible for participation in the study. This allowed human immunodeficiency virus (HIV)-infected patients with higher CD4 counts to be entered into the trial. The development of R90-001-01 was very similar to the development of R89. Multiple meetings and conference calls within the AIDS Clinical Trials Group system reviewed draft protocols, including reviews by representatives from the Medical Branch of the National Institute of Allergy and Infectious Diseases (NIAID) and the Food and Drug Administration (FDA). The protocol was originally designed to establish FIAU as a potential anti-CMV drug. HIV-infected patients were to receive FIAU syrup three times daily at dosages of either 1.0, 1.7, 3.0, or 5.0 mg/kg/day. Cohorts of 10 patients each were to be enrolled successively in each dosage group, beginning at the 1 mg/kg/day dosage. During protocol development, several reviewers suggested evaluating the potential role of FIAU in the treatment of hepatitis B virus (HBV) infection, citing the potent in vitro activity of both FIAC and FIAU against HBV (Hantz, Allaudeen, Ooka, De Clercq and Trepo, 1984). FIAC also had been shown more effective than Ara-A in reducing circulating viral DNA in woodchucks infected with a HBV closely related to that infecting man (Fourel, Hantz, Watanabe, Jacquet, Chomel and Trepo, 1990). By mid-August, an amendment was created (Amendment 1) which allowed investigators to enroll HBV infected persons after an initial cohort of non-HBV infected individuals had been enrolled. Based on the knowledge that patients with chronic HBV infection often have chronic elevations in their liver enzymes, Amendment 1 also changed the AST entry criterion to allow patients with up to 5 times the

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Review of the Fialuridine (FIAU) Clinical Trials upper limit of normal (from 1.5 times) to be enrolled into the study. The amendment also inserted 1-week and 4-week posttreatment follow-up clinical chemistry evaluations to capture any posttreatment flares that might occur in the HBV-treated patients. These flares are characterized by development of a several fold elevation in transaminase levels concomitant with successful inhibition of HBV DNA and may occur several weeks after termination of drug therapy. The protocol was reviewed by the IRBs at the University of Washington and the University of California, San Diego and was approved by both. During this review the ICD was evaluated and judged to be in compliance with national standards. The possibility of gastrointestinal disturbances, bone marrow toxicity, neurologic toxicity (including confusion and seizures), and cardiac toxicity, which was noted in animal studies, were all mentioned in the ICD (Appendix D). The possible development of polymyositis, an issue not raised in the FIAC (R89) ICD, was explicitly mentioned in the R90 ICD on the basis of the reversible myositis seen in the FIAC study. Faxed weekly summary data and interim conference calls (every 2 to 3 weeks) were used throughout the R90 study. In addition, as with the R89 study, Oclassen periodically visited the study site to review the charts of study patients. The first 10 patients in this study were enrolled at the University of Washington site (initial dosage 1 mg/kg/day), with the first patient receiving drug in October 1990. These patients completed treatment without significant clinical adverse experiences. Therefore on the basis of the protocol, the dose was escalated to 1.7 mg/kg/day. The first patient receiving this higher dose experienced nausea and fatigue. The next patient who received this dose also developed significant gastrointestinal symptoms and fatigue. This information was shared with the rest of the study team via fax memorandum, and a conference call was convened to discuss these issues. It was determined that, should a third patient experience similar symptoms at this dosage level, further enrollment in this study at dosages higher than 1 mg/kg/day would cease. Patient 214, who was enrolled on April 19, 1991, became the third patient to develop gastrointestinal intolerance, and it was determined that no further patients should be enrolled in this study. As a result of this close monitoring system, the MTD of FIAU was determined with only 13 patients enrolled in the study. It was now clear that neither FIAC nor FIAU would ever be developed as an effective anti-CMV drug. There was no evidence of anti-CMV activity even at doses associated with clinically significant gastrointestinal symptoms. However, on the basis of the known in vitro anti-HBV activity of the compound, the team decided to further pursue the role of FIAU in patients coinfected with HIV and HBV. During the months that the first 13 patients were being accrued into the R90 study, Stephen Straus at the Intramural Research Division of NIAID had submitted the R90 protocol to the NIAID IRB. The IRB carefully reviewed the protocol, and in November 1990, after Straus responded in writing to all of the board's stipulations, the NIAID IRB approved the protocol for implementation at the National Institutes of Health. Stephen Straus is Chief of the Laboratory of Clinical Investigation, Medical Virology Section of NIAID at the Bethesda, Maryland, campus of NIH. Like Douglas Richman and Lawrence Corey, Straus had been integrally involved in the development of drugs designed to treat human herpes virus infections, such as vidarabine and acyclovir. Straus is also a bench research scientist with special interest in the pathogenesis of herpes simplex virus disease. As

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Review of the Fialuridine (FIAU) Clinical Trials a member of the NIH staff, he has participated in dozens of clinical studies and was well qualified to lead the R90 study at the NIH. With the new focus on potential anti-HBV activity and reduced dosage of FIAU (a maximum of 1 mg/kg daily), the first patient enrolled at NIH (patient 401) began treatment on April 16, 1991. In less than 2 weeks, a marked decrease in the patient's serum HBV DNA polymerase level was noted. This information was reported to all other investigators via fax. At this dose the drug showed similar activity in three additional patients. When the results were reviewed during the conference call, the investigators agreed that this was the most striking effect on HBV they had ever seen. On the basis of the anticipated need to administer prolonged therapy to patients with chronic HBV infection and the knowledge that the 1 mg/kg dose was close to the MTD, the investigators decided to convert the trial into a dose de-escalating study, to find the lowest dose still effective against HBV. Therefore, the next cohort entered into the study would receive a dose of 0.5 mg/kg and the final group would receive a dose of 0.1 mg/kg, 1/10th of the original dose. It was anticipated that cohorts of approximately 10 to 12 patients per dose group would be enrolled. All of the early HBV data and the decision to convert the study into a dose deescalation design was reviewed by the Viral Pathogen Study Group of ACTG and by the Antiviral Drug Division of the Food and Drug Administration. Both concurred with the decision to continue studying the drug as an anti-HBV agent in this fashion. Throughout the remainder of 1991 and into the spring of 1992, several interim reviews were undertaken by the IRBs at all three participating institutions via requisite status reports submitted for routine review as well as through review of the amendments required to establish the dose deescalation component of the study. By June 15, 1992, the last HIV-positive, HBV-positive patient was entered into the 0.1 mg/kg dose cohort, and by June 29 the last dose of FIAU in study R90 was administered. In total, 4 of the 43 patients were enrolled at UCSD, 25 patients were enrolled at the University of Washington (12 non-HBV infected and 13 HBV-infected), and 14 (all HBV-infected) patients were enrolled at the NIH Clinical Center. Striking reductions in circulating HBV DNA levels were noted in most patients, with the majority of patients showing decreases in their circulating HBV DNA levels to less than the lower limits of the measurement technology. More importantly, the level of virus remained suppressed for up to 4 to 6 weeks after the drug was discontinued. The experience with other nucleoside analogs such as vidarabine resulted in only a partial reduction in circulating HBV DNA levels and rapid reversal upon cessation of the drug. As such, FIAU represented the most potent anti-HBV agent studied to date. On the basis of these findings, the protocol was modified to allow retreatment, for an additional 14 days, of four patients who displayed recrudescence of DNA polymerase levels following their initial treatment. The length of follow-up after drug was stopped was 4 weeks. Several patients in the R90 study developed elevations in liver function enzyme levels while on treatment. Most notably, patients 216, 221, and 224 exhibited two- to three-fold elevations in transaminase values in the second or third week of the study. All three of these HIV-positive individuals had coinfection with HBV; two of the patients (patients 221 and 224) had received the lowest dose of drug (0.1 mg/kg/day), while the third patient (patient 216) received an intermediate dose of 0.5 mg/kg/day. In each of these individuals, no clinical signs

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Review of the Fialuridine (FIAU) Clinical Trials of hepatic dysfunction were noted and the increases in transaminase levels in liver function tests were interpreted as flares associated with the clearance of HBV. Three patients died within 6 months of receiving their last dose of FIAU. All three patients had received a second course of FIAU treatment for their chronic HBV disease. Patient 401 was an individual with underlying HIV, HBV, hepatitis C virus, and hepatitis D virus infections. He was initially dosed from April 16 to April 30, 1991, and was assigned to receive 1 mg of FIAU per kg daily in three equal doses. Through an error in dosing, the subject actually received 10 times the scheduled initial dose on the first study day (i.e., 3.3 mg/kg rather than 0.33 mg/kg). He suffered no apparent ill effects from this round of dosing and approximately 13 months later was retreated for 13 days, from May 23 to June 4, 1992 (bringing his total dose to 2,437 mg). Three months after his last FIAU dose, he was hospitalized with jaundice, ascites, and hepatic encephalopathy. His AST and ALT levels were 203 and 216 units/liter, respectively, his bilirubin level was 6.3 mg/dl (ultimately rising to 31 mg/dl), and his CD4 count was 669 cells/mm3 The patient continued on a downhill course, ultimately dying on October 18, 1992, approximately 5 months after receiving his last FIAU dose. At autopsy, the liver exhibited cirrhosis with bridging fibrosis, regenerative nodules, periportal inflammation, cholangiolitis, and cholestasis. There was no evidence of steatosis and no lactic acidosis was observed during the terminal phases of his disease. The patient was judged by the investigators to have died from his underlying diseases. Patient 406 was a 45-year-old HIV-infected male with concomitant HBV disease who had participated in previous clinical trials of interferon, ribivarin, and ampligen. In addition he had received several therapies for HIV between 1988 and June 1991, including AZT and ddC. He received 1 mg of FIAU per kg/day for 14 days, from June 4 to June 17, 1991, before and after which his personal physician prescribed ddC for his HIV infection, although ddC was replaced by AZT in the fall of 1991 because of peripheral neuropathy. The patient was retreated with FIAU approximately 1 year later (June 1992) for 17 days at a dose of 0.5 mg/kg/day (total dose, 1,718 mg). Treatment was discontinued because of pain in the feet. After 2 weeks of follow-up the patient missed all further appointments at NIH. The patient's HIV medication was switched from AZT to ddI in July by his local physician, and 6 weeks later he developed fulminant hemorrhagic pancreatitis, ascribed to the ddI in combination with his HBV and HIV infections. He was admitted to a local hospital with an amylase level of 1,166 and a lipase level of >4,000. Despite discontinuation of ddI and aggressive therapy, he died secondary to severe hemorrhagic pancreatitis. NIH investigators were informed of his death 2 weeks later. On autopsy, the entire pancreas was involved with necrosis and hemorrhage extending into the retroperitoneum. Importantly, the liver demonstrated only minimal steatosis with fibrosis around the portal triads. There was no report of lactic acidosis in this patient. The third death was patient 408, a 38-year-old HIV- and HBV-infected male with cirrhosis documented by liver biopsy in 1988 who received 1 mg of FIAU per kg/day for 12 days beginning on November 3, 1991. Approximately 2 months later he received a second course of FIAU at the same dosage level (total dose, 2,534 mg). Within a week after stopping FIAU, the patient was started on a combination of ddI and AZT and he continued to take them for approximately 2 months of therapy (until March 15, 1992), at which time the drugs were stopped in response to abdominal bloating and discomfort. In April 1992, the patient was

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Review of the Fialuridine (FIAU) Clinical Trials diagnosed as having hepatic failure on the basis of the physical findings of jaundice and ascites. In early May he suffered an acute upper gastrointestinal hemorrhage secondary to cirrhosis and associated esophageal varices and coagulopathy. Despite aggressive resuscitative measures, the patient died on May 16, 1992. Autopsy showed micro-and macronodular cirrhosis, pancreatic fibrosis, and esophageal varices. Microscopic examination showed marked obstruction of hepatocytes but no evidence of steatosis. The patient did not develop any lactic acidosis throughout the course of his illness, and his peak AST and ALT levels were 284 and 154 units/liters, respectively. The investigators were not aware of this patient's death until July 1993, at the time that the patients in the PPPC study were being diagnosed with hepatic failure. An additional patient, patient 409, developed pancreatitis within 6 months of being dosed with FIAU and survived the episode. The patient is a 36-year-old male coinfected with HIV and HBV who received 0.5 mg of FIAU per kg for 2 weeks in December 1991. In late April he received the drug at the same dose another 14 days (total dose, 1,663 mg). In late May the patient was started on ddI therapy. In late July he developed abdominal pain and subsequent volume depletion. On August 10, 1992, he was admitted to the hospital and a diagnosis of pancreatitis was established. His pancreatitis resolved after ddI was discontinued. The investigators concluded that the pancreatitis was most likely due to the ddI therapy. COMMENT Like the R89 trial, this was a carefully performed Phase I clinical study that underwent extensive internal and external peer review prior to initiation. The real-time data and safety assessments via fax and conference calls once again resulted in remarkably efficient identification of an MTD and modification of the protocol into a dose-deescalating study, with a shift in focus from the study of CMV disease to one of HBV infection. A unique aspect of this study is the availability of a relative ''control'' group of non-HBV-infected individuals, all of whom received the highest dosages of drug (1.0 to 1.7 mg/kg/day). None of the individuals in this non-HBV-infected control group experienced any elevation in transaminase levels >3 times the upper limit of normal at any time, and none of these patients had elevations of >1.7 times the upper limit of normal at the end of the study (day 14) (Table 6-1). On the basis of the dramatic fall in HBV DNA levels and the anticipation of a flare in transaminase levels associated with successful treatment of HBV, the investigators judged the elevations in transaminase levels not to be "serious or unexpected adverse events" that require immediate formal reporting to the sponsor as such. In retrospect, with the additional perspective of the control group, this judgment appears sound and appropriate. Even if one judged these elevations in liver enzyme levels to be a serious or unexpected adverse event, from a functional standpoint the sponsor and FDA were kept fully informed of all laboratory values the laboratory reports faxed to them. Moreover, discussion of abnormal laboratory values occurred during conference calls in which the investigators, the sponsor, the NIAID Program Office, and FDA participated. With regard to the patients who died, patient 401 showed no evidence of steatosis or lactic acidosis at the time of death and had extensive cirrhosis consistent with advanced viral

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Review of the Fialuridine (FIAU) Clinical Trials TABLE 6-1 Liver Function Test Results of non-HBV-Infected Patients in Trial R90-001-01 Patient No. Peak/Base ALT Level Peak ALT Level Peak/Base AST Level Peak AST 201 3.0 135 2.7 72 202 1.5 10 1.2 36 203 2.8a 27 1.3 21 204 1.2 91 1.3 57 205 1.7 53 1.5 40 206 1.7 23 1.2 29 207 1.3 28 0.7 25 208 2.6 46 1.7 33 209 1.9 32 1.9 26 210 2.0 86 1.8 51 211 2.0 41 1.4 29 212 1.0 10 1.4 17 214 0.9 31 0.9 22 a Highest value was within normal reference level SOURCE: Corey, 1994 hepatitis. Therefore he could quite appropriately be judged as having died as a result of his underlying hepatic disease, which was a result of hepatitis C and D virus infections as well as HBV infection. Patient 406 clearly died from severe pancreatitis. However, on the basis of the recent institution of ddI therapy and the known association of pancreatitis with ddI therapy, the investigators attributed the pancreatitis as being secondary to ddI therapy. It is difficult even in retrospect to argue with this assessment. It is well known that ddI causes pancreatitis, which may result in a fatal outcome. Whether FIAU aggravated or accentuated the development or course of the pancreatitis in this patient will never be known. Patient 408 died of progressive liver disease 4 months after his second course of FIAU therapy. He had a long-standing history of cirrhosis, and it is plausible that his death was due to progression of his underlying disease. In support of this assessment is the histologic finding at autopsy of advanced cirrhosis without evidence of microvesicular steatosis. In any case, investigators were not informed of this death until July of 1993, after trial PPPC was terminated.